This year the Genetics Services Research Unit of SBRB conducted and analyzed data from a randomized controlled study of two clinical arms returning carrier results from genome sequencing. This study resulted in two different analyses and publications. Further, we developed a new taxononmy and assessment of uncertainty in genome sequencing. 1. A critical bottleneck in clinical genomics is the mismatch between large volumes of results and the availability of knowledgeable professionals to return them. We aimed to test whether a web-based platform is non-inferior to a genetic counselor for educating patients about their carrier results from exome sequencing. A randomized non-inferiority trial from 2014-2016 was used to compare the web-based platform to a genetic counselor. Surveys were administered at baseline (T1), immediately following disclosure (T2), at one month (T3) and six months later (T4) to participants of post-reproductive age who expressed strong interest in learning their carrier results.Of the eligible participants, 571 were heterozygous for a variant in at least one gene that causes a phenotype inherited in an autosomal recessive pattern. After 462 participants (81%) provided consent and were randomized, all but three participants (N=459) completed T2 surveys following education and counseling; 87% completed T3 and 85% completed T4 surveys. We designed a web-based platform that integrated education on carrier results with personal test results to directly parallel disclosure education by a genetic counselor. The sessions took 21 and 27 minutes, respectively. Our primary outcomes were knowledge, test-specific distress, decisional conflict. Participants were on average 63 years old, and predominantly, well-educated, non-Hispanic white married parents. The web platform was non-inferior to the genetic counselor on outcomes assessed at T3 and T4: knowledge (dmean=-0.18; lower limit of 97.5% CI=-0.63; non-inferiority margin (NI)=-1), test-specific distress (dmedian=0; upper limit of 97.5% CI=0; NI=1), and decisional conflict about choosing to learn results (dmean=1.18; upper limit of 97.5% CI=2.66; NI=6). There were no significant differences detected between modes of education delivery in disclosure rates to spouses, children, or siblings. This trial demonstrates non-inferiority of web-based return of carrier results among parents of reproductive age children. Replication studies among more diverse populations are needed to determine generalizability. Yet return of results via a web-based platform may be sufficient for subsets of test results, reserving genetic counselors for return of results with a higher health threat. 2. Exome sequencing generates uncertain results. How individuals perceive the uncertainties may affect clinical utility of receipt of results. For this study participants were randomized to receive carrier results from sequencing by a web-based platform (n=126) or a genetic counselor (n=130). Participants received on average two results. Analysis of variance was used to assess group differences over time in affective, evaluative, and clinical uncertainties. Reductions from baseline in affective uncertainty (x=0.78, 95% CI: 0.53, 1.02) and evaluative uncertainty (x=0.69, 95% CI: 0.51, 0.87) followed both interventions regardless of randomization. Only those in the genetic counselor arm reported reduced clinical uncertainty one month following disclosure (x=0.53, 95% CI: 0.29, 0.78), which may reflect these participants' opportunity ask questions during education sessions. Additionally, clinical and evaluative uncertainties accounted for variance in decisional uncertainty about receiving results in the web platform arm, which may be related to residual questions reported by these participants. In return of carrier results, both genetic counselors and web platforms may reduce affective and evaluative uncertainties, but it may be that only disclosure by a genetic counselor reduces clinical uncertainty. This suggests that reinforcing clinical information and outlets for unanswered questions may be key to optimizing patient outcomes. 3. Clinical next generation sequencing (CNGS) is introducing new opportunities and challenges into the practice of medicine. Simultaneously, these technologies are generating uncertainties of unprecedented scale that laboratories, clinicians, and patients are required to address and manage. We describe in this report the conceptual design of a new taxonomy of uncertainties around the use of CNGS in health care. Interviews to delineate the dimensions of uncertainty in CNGS were conducted with genomics experts, and themes were extracted in order to expand upon a previously published three-dimensional taxonomy of medical uncertainty. In parallel we developed an interactive website to disseminate the CNGS taxonomy to researchers and engage them in its continued refinement. The proposed taxonomy divides uncertainty along three axes: source, issue, and locus, and further discriminates the uncertainties into five layers with multiple domains. Using a hypothetical clinical example, we illustrate how the taxonomy can be applied to findings from CNGS and used to guide stakeholders through interpretation and implementation of variant results. The utility of the proposed taxonomy lies in promoting consistency in describing dimensions of uncertainty in publications and presentations, to facilitate research design and management of the uncertainties inherent in the implementation of CNGS. 4. Expectations of results from genome sequencing by end users are influenced by perceptions of uncertainty. This study aimed to assess uncertainties about sequencing by developing, evaluating, and implementing a novel scale. The Perceptions of Uncertainties in Genome Sequencing (PUGS) scale comprised ten items to assess uncertainties within three domains: clinical, affective, and evaluative. Participants (n=535) from the ClinSeq NIH sequencing study completed a baseline survey that included the PUGS; responses (mean=3.4/5, SD=0.58) suggested modest perceptions of certainty. A confirmatory factor analysis identified factor loadings that led to elimination of two items. A revised eight-item PUGS scale was used to test correlations with perceived ambiguity (r=-0.303, p<0.001), attitudinal ambivalence (r=-0.111, p=0.011), and ambiguity aversion (r=-0.093, p=0.033). Results support nomological validity. A correlation with the MICRA uncertainty subscale was found among 175 cohort participants who had received results (r=-0.335, p<0.001). Convergent and discriminant validity were also satisfied in a second sample of 208 parents from the HudsonAlpha CSER Project who completed the PUGS (mean=3.4/5, SD=0.72), and configural invariance was supported across the two datasets. As such, the PUGS is a promising scale for evaluating perceived uncertainties in genome sequencing, which can inform interventions to help patients form realistic expectations of these uncertainties.